February 10, 2015

Diagram of the brain of a person with Alzheimer's Disease. Credit: Wikipedia/public domain.

Scientists from the Gladstone Institutes and the University of California, San Francisco report in the Journal of Neuroscience that raising levels of the life-extending protein klotho can protect against learning and memory deficits in a mouse model of Alzheimer's disease. Remarkably, this boost in cognition occurred despite the accumulation of Alzheimer-related toxins in the brain, such as amyloid-beta and tau.

Klotho decreases naturally with aging, which also leads to a decline in cognitive ability. An earlier study from these researchers revealed that having a genetic variant that increases klotho levels is associated with better cognition in normal, healthy individuals, and experimentally elevating klotho in mice enhances learning and memory. However, klotho's influence in the face of aging-related cognitive disorders like Alzheimer's disease was unclear.

To test klotho's protective capacity, the scientists created a mouse model of Alzheimer's disease that produced higher levels of this protein throughout the body. Ordinarily, Alzheimer's-model mice have cognitive deficits, abnormal brain activity, and premature death, but raising klotho levels ameliorated these problems. The cognition-enhancing effects of the protein were powerful enough to counteract the effects of Alzheimer-related toxins, whose levels were unchanged.

"It's remarkable that we can improve cognition in a diseased brain despite the fact that it's riddled with toxins," says lead author Dena Dubal, MD, PhD, an assistant professor of neurology and the David A. Coulter Endowed Chair in Aging and Neurodegenerative Disease at UCSF. "In addition to making healthy mice smarter, we can make the brain resistant to Alzheimer-related toxicity. Without having to target the complex disease itself, we can provide greater resilience and boost brain functions."

Klotho's benefits may be due to its effect on a certain type of neurotransmitter receptor in the brain, called NMDA, that is crucially involved in learning and memory. While Alzheimer's impairs NMDA receptors, the mice with klotho elevation maintained normal receptor levels. In addition, these mice had more GluN2B—a subunit of NMDA—than control animals. This increase may have contributed to the protective effects of klotho, counteracting the detrimental impact of Alzheimer-related toxicity on the brain.

"The next step will be to identify and test drugs that can elevate klotho or mimic its effects on the brain," says senior author Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease and the Joseph B. Martin Distinguished Professor of Neuroscience at UCSF. "We are encouraged in this regard by the strong similarities we found between klotho's effects in humans and mice in our earlier study. We think this provides good support for pursuing klotho as a potential drug target to treat cognitive disorders in humans, including Alzheimer's disease."

Related Stories

People who carry a variant of a gene that is associated with longevity also have larger volumes in a front part of the brain involved in planning and decision-making, according to researchers at UC San Francisco.

A scientific team led by the Gladstone Institutes and UC San Francisco has discovered that a common form of a gene already associated with long life also improves learning and memory, a finding that could have implications ...

Boston University School of Medicine researchers may have found a way to delay or even prevent Alzheimer's disease (AD). They discovered that pre-treatment of neurons with the anti-aging protein Klotho can prevent neuron ...

Decreased blood levels of a kidney-derived protein called Klotho increases the risk of heart disease in mice with kidney disease, according to a study appearing in an upcoming issue of the Journal of the American Society ...

A study by scientists from the Gladstone Institutes shows that decreasing the number of A2A adenosine receptors in a particular type of brain cells called astrocytes improved memory in healthy mice. What's more, reducing ...

Researchers at Boston University School of Medicine (BUSM) led by Carmela Abraham, PhD, professor of biochemistry, along with Cidi Chen, PhD, and other collaborators, report that the protein Klotho plays an important role ...

Recommended for you

Cedars-Sinai neuroscience investigators have found that Alzheimer's disease affects the retina—the back of the eye—similarly to the way it affects the brain. The study also revealed that an investigational, noninvasive ...

By the time you start losing your memory, it's almost too late. That's because the damage to your brain associated with Alzheimer's disease (AD) may already have been going on for as long as twenty years. Which is why there ...

A new machine learning program developed by researchers at Case Western Reserve University appears to outperform other methods for diagnosing Alzheimer's disease before symptoms begin to interfere with every day living, initial ...

In a study looking at brain scans of people with mild loss of thought and memory ability, Johns Hopkins researchers report evidence of lower levels of the serotonin transporter—a natural brain chemical that regulates mood, ...

People with specific mutations in the gene TREM2 are three times more likely to develop Alzheimer's disease than those who carry more common variants of the gene. But until now, scientists had no explanation for the link.

Researchers from Yale University School of Medicine have discovered that defects in the transport of lysosomes within neurons promote the buildup of protein aggregates in the brains of mice with Alzheimer's disease. The study, ...